James L. Lordan

Epithelial-mesenchymal interactions in the pathogenesis of asthma.

Abstract During lung development, repair, and inflammation, local production of cytokines (eg, transforming growth factor-β) and growth factors (eg, epidermal growth factor) by epithelial and mesenchymal cells mediate bidirectional growth control effectively creating an epithelial-mesenchymal trophic unit. In asthma the bronchial epithelium is highly abnormal, with structural changes involving separation of columnar cells from their basal attachments and functional changes including increased expression and release of proinflammatory cytokines, growth factors, and mediator-generating enzymes. Beneath this damaged structure there is an increase in the number of subepithelial myofibroblasts that deposit interstitial collagens causing thickening and increased density of the subepithelial basement membrane. Our recent studies suggest that the extent of epithelial damage in asthma may be the result of impaired epidermal growth factor receptor–mediated repair. In view of the close spatial relationship between the damaged epithelium and the underlying myofibroblasts, we propose that impaired epithelial repair cooperates with the TH2 environment to shift the set point for communication within the trophic unit. This leads to myofibroblast activation, excessive matrix deposition, and production of mediators that propagate and amplify the remodeling responses throughout the airway wall. (J Allergy Clin Immunol 2000;105:193-204.)

Cooperative Effects of Th2 Cytokines and Allergen on Normal and Asthmatic Bronchial Epithelial Cells

In sensitized individuals, exposure to allergens such as Dermatophagoides pteronyssinus (Der p) causes Th2 polarization and release of cytokines, including IL-4 and IL-13. Because Der p extracts also have direct effects on epithelial cells, we hypothesized that allergen augments the effects of Th2 cytokines by promoting mediator release from the bronchial epithelium in allergic asthma. To test our hypothesis, primary bronchial epithelial cultures were grown from bronchial brushings of normal and atopic asthmatic subjects. RT-PCR showed that each culture expressed IL-4Rα, common γ-chain, and IL-13Rα1, as well as IL-13Rα2, which negatively regulates IL-13 signaling; FACS analysis confirmed IL-13Rα2 protein expression. Exposure of epithelial cultures to either Der p extracts, TNF-α, IL-4, or IL-13 enhanced GM-CSF and IL-8 release, and this was partially suppressible by corticosteroids. Simultaneous exposure of the epithelial cultures to IL-4 or IL-13 together with Der p resulted in a further increase in cytokine release, which was at least additive. Release of TGF-α was also increased by TNF-α and combinations of IL-4, IL-13, and Der p; however, this stimulation was only significant in the asthma-derived cultures. These data suggest that, in an allergic environment, Th2 cytokines and allergen have the potential to sustain airway inflammation through a cooperative effect on cytokine release by the bronchial epithelium. Our novel finding that IL-4, IL-13, and allergen enhance release of TGF-α, a ligand for the epidermal growth factor receptor that stimulates fibroblast proliferation and goblet cell differentiation, provides a potential link between allergen exposure, Th2 cytokines, and airway remodelling in asthma.

Anti-Inflammatory Drugs in Asthma: The Pathophysiology of Asthma

Asthma is a chronic condition characterised by widespread, variable and reversible airflow obstruction which is either spontaneous or pharmacologically induced. The underlying pathophysiological feature of asthma is increased airway responsiveness which develops on a basis of diffuse bronchial inflammation. The prevalence of asthma is increasing worldwide despite improved treatment which has resulted from a more comprehensive understanding of its pathogenesis [1]. In most countries asthma affects between 4 and 8% of the population, with a trend towards an increase in morbidity as judged by increased hospital admissions [2]. The reasons for this are unclear, but environmental factors such as indoor and outdoor air pollution and changes in lifestyle are considered to be amongst the contributing factors.